Risk of Migraine after Traumatic Brain Injury and Effects of Injury Management Levels and Treatment Modalities: A Nationwide Population-Based Cohort Study in Taiwan

Traumatic brain injury (TBI) causes several long-term disabilities, particularly headaches. An association between TBI and subsequent migraine has been reported. However, few longitudinal studies have explained the link between migraine and TBI. Moreover, the modifying effects of treatment remain unknown. This retrospective cohort study used records from Taiwan’s Longitudinal Health Insurance Database 2005 to evaluate the risk of migraine among patients with TBI and to determine the effects of different treatment modalities. Initially, 187,906 patients, aged ≥ 18 years, who were diagnosed as TBI in 2000, were identified. In total, 151,098 patients with TBI and 604,394 patients without TBI were matched at a 1:4 ratio according to baseline variables during the same observation period. At the end of follow-up, 541 (0.36%) and 1491 (0.23%) patients in the TBI and non-TBI groups, respectively, developed migraine. The TBI group exhibited a higher risk of migraine than the non-TBI group (adjusted HR: 1.484). Major trauma (Injury Severity Score, ISS ≥ 16) was associated with a higher migraine risk than minor trauma (ISS < 16) (adjusted HR: 1.670). However, migraine risk did not differ significantly after surgery or occupational/physical therapy. These findings highlight the importance of long-term follow-up after TBI onset and the need to investigate the underlying pathophysiological link between TBI and subsequent migraine.


Introduction
Traumatic brain injury (TBI) is defined as the disruption of brain function or other evidence of brain pathology caused by an external physical force [1]. TBI results in more deaths and disabilities than any other traumatic insult worldwide [2]. The estimated annual occurrence of TBI varies widely, ranging from 2.5 million in the European Union to 3.5 million in the USA [3]. Due to increased road traffic, the incidence is typically higher in developing countries [4][5][6]. For example, in India, TBI causes an estimated 1 million disabilities annually and accounts for one fatality every three minutes [3].
TBI causes not only short-term impairment, but also persistent and even life-long consequences [7]. Negative outcomes following TBI include persistent postconcussive

Study Design and Sampled Participants
Of the 1,984,250 patients with outpatient or inpatient records in the LHID2005 claims data in 2000 (Figure 1), we identified 187,906 patients diagnosed as having TBI, according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM; 2000-2015) diagnostic codes, with the diagnosis being made at least thrice in the outpatient department (OPD), once in the emergency department, or once on admission. Patients who received a TBI diagnosis in any specialty were included. Patients who were younger than 18 years or who had a history of TBI or other diseases that may cause vertigo or dizziness before the index date were excluded. Moreover, patients diagnosed as having migraine before the index date and those with incomplete demographic data were excluded. In total, 151,098 patients with newly diagnosed TBI were enrolled into the TBI cohort. For each patient in the TBI cohort, four patients without a history of TBI were selected from the remaining records by propensity score matching, according to sex, age, comorbidities, and index date (non-TBI cohort). The exclusion criteria were the same for both the cohorts. The matched non-TBI cohort included 604,394 patients, and the date of the records used for their selection served as the index date. The diagnostic codes for the inclusion and exclusion variables are presented in Appendix A Table A1.
selected from the remaining records by propensity score matching, according to sex, age, comorbidities, and index date (non-TBI cohort). The exclusion criteria were the same for both the cohorts. The matched non-TBI cohort included 604,394 patients, and the date of the records used for their selection served as the index date. The diagnostic codes for the inclusion and exclusion variables are presented in Appendix Table A1.

Outcome Measurement
Both the cohorts were followed up from the index date to the date of migraine onset, withdrawal from the NHI program, or the end of follow-up. For outcome measurement, migraine was defined using the ICD-9-CM diagnostic code 346 and the ICD-10-CM diagnostic code G43. Patients who received a diagnosis of migraine from a neurologist or an otolaryngologist were enrolled into this study. The cumulative incidence of migraine was estimated according to the TBI status using the Kaplan-Meier method, and differences between the cumulative incidence rates were compared using a log-rank test. Moreover, Cox proportional hazards models were used to compute the crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for migraine between the TBI and non-TBI groups and between different TBI subgroups. Injury severity scores (ISS) [32,33] were used to assess the severity of injury and to predict mortality, morbidity, and length of hospital stay. The ISS ranges from 1 to 75. As per the NHI program in Taiwan, ISS ≥ 16 denotes the presence of major trauma and a catastrophic illness. Patients with any defined catastrophic illness can benefit from copayment exemptions.

Outcome Measurement
Both the cohorts were followed up from the index date to the date of migraine onset, withdrawal from the NHI program, or the end of follow-up. For outcome measurement, migraine was defined using the ICD-9-CM diagnostic code 346 and the ICD-10-CM diagnostic code G43. Patients who received a diagnosis of migraine from a neurologist or an otolaryngologist were enrolled into this study. The cumulative incidence of migraine was estimated according to the TBI status using the Kaplan-Meier method, and differences between the cumulative incidence rates were compared using a log-rank test. Moreover, Cox proportional hazards models were used to compute the crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for migraine between the TBI and non-TBI groups and between different TBI subgroups. Injury severity scores (ISS) [32,33] were used to assess the severity of injury and to predict mortality, morbidity, and length of hospital stay. The ISS ranges from 1 to 75. As per the NHI program in Taiwan, ISS ≥ 16 denotes the presence of major trauma and a catastrophic illness. Patients with any defined catastrophic illness can benefit from copayment exemptions.

Potential Confounders
We adjusted for the following confounders: sex, age/age group, geographic location in Taiwan, urbanization level, insurance premium, season, and level of care. Individuals with or without the comorbidities listed in Table 1, on or before the index date, were stratified by the aforementioned confounders for comparison.

Subgourp Analysis
Subgroup analysis was performed according to TBI treatments to determine the effect of the interventions on migraine risk. Brain surgery, involving microvascular decompression, craniotomy or cranioplasty, ventriculostomy, hematoma removal, endarterectomy, and bypass surgery, were included as surgical treatment. Moreover, chronic rehabilitation programs included occupational therapy (OT) and physical therapy (PT).

Statistical Analysis
All statistical analyses were performed using IBM SPSS Statistics version 22 (IBM, Armonk, NY, USA). The chi-squared test and Student's t-test were used to assess the distributions of categorical and continuous variables, respectively. Multivariate Cox proportional hazards regression analysis was conducted to determine the risk of migraine. The results are presented as HRs and 95% CIs. The differences in the risk of migraine between the TBI and non-TBI cohorts were assessed using the Kaplan-Meier method and log-rank tests. A two-tailed p value of <0.05 was considered significant.

Baseline Characteristics
The baseline characteristics of the TBI and non-TBI cohorts are presented in Table 1. The mean age of the TBI cohort was 44.43 ± 18.55 years. No significant differences in sex, age, or comorbidities were noted between the TBI and non-TBI cohorts after propensity score matching. The average follow-up period was 10.75 and 10.88 years for the TBI and non-TBI cohorts, respectively ( Table 2). Appendix A Table A2 presents the characteristics of the TBI and non-TBI cohorts at the end of follow-up. At the end of follow-up, 541 (0.36%) of 151,098 TBI patients and 1419 (0.23%) of 604,394 non-TBI controls had developed migraine (p < 0.001). Kaplan-Meier analysis revealed that the cumulative risk of migraine significantly differed between the TBI and non-TBI cohorts over the 18-year follow-up period (log-rank test, p < 0.001, Figure 2).

Kaplan-Meier Model for Assessing the Cumulative Risk of Migraine
At the end of follow-up, 541 (0.36%) of 151,098 TBI patients and 1419 (0.23%) of 604,394 non-TBI controls had developed migraine (p < 0.001). Kaplan-Meier analysis revealed that the cumulative risk of migraine significantly differed between the TBI and non-TBI cohorts over the 18-year follow-up period (log-rank test, p < 0.001, Figure 2).

HRs for Migraine in the TBI Cohort
Appendix Table A3 lists the factors that were associated with migraine by the end of follow-up in the Cox regression model. In the TBI cohort, the crude HR for migraine was 1.688 (95% CI: 1.454-2.006, p < 0.001). After adjustment for age, sex, comorbidities, insurance premium, geographic location, urbanization level, and level of care, the adjusted HR was 1.484 (95% CI: 1.276-1.724, p < 0.001). The TBI cohort exhibited a higher risk of migraine than the non-TBI cohort, as revealed by subgroup analyses stratified by sex, age group, insurance premium, comorbidities, urbanization level, geographic location, and level of care (Appendix Table A4). Table 3 presents the results of Cox regression analyses of migraine subtypes in the TBI cohort. No significant differences were noted between the risk of migraine with and

HRs for Migraine in the TBI Cohort
Appendix A Table A3 lists the factors that were associated with migraine by the end of follow-up in the Cox regression model. In the TBI cohort, the crude HR for migraine was 1.688 (95% CI: 1.454-2.006, p < 0.001). After adjustment for age, sex, comorbidities, insurance premium, geographic location, urbanization level, and level of care, the adjusted HR was 1.484 (95% CI: 1.276-1.724, p < 0.001). The TBI cohort exhibited a higher risk of migraine than the non-TBI cohort, as revealed by subgroup analyses stratified by sex, age group, insurance premium, comorbidities, urbanization level, geographic location, and level of care (Appendix A Table A4). Table 3 presents the results of Cox regression analyses of migraine subtypes in the TBI cohort. No significant differences were noted between the risk of migraine with and without aura. Moreover, no significant differences were noted in the diagnoses made by otolaryngologists and neurologists. Adjusted HR = adjusted hazard ratio (adjusted for the variables listed in Table A2); CI = confidence interval. Table 4 presents the results of Cox regression analyses of TBI subtypes in the TBI cohort. Regarding the severity of injuries, the risk of migraine with ISS ≥ 16 was higher in the TBI cohort than the risk of migraine with ISS < 16 (adjusted HR: 1.670, 95% CI: 1.325-2.011, p < 0.001). Hospitalized patients exhibited a significantly higher risk of subsequent migraine than those visiting the OPD (adjusted HR: 1.557, 95% CI: 1.203-1.837, p < 0.001). Adjusted HR = adjusted hazard ratio (adjusted for the variables listed in Table A3); CI = confidence interval. * Compared with those with brain surgery. Table 4 presents the results of Cox regression analyses of treatment modalities in the TBI cohort. No significant differences were noted between the TBI subgroups with and without brain surgery. Similarly, no significant differences were noted between the TBI subgroups with and without OT/PT and pharmacological treatment. The percentage of participants who received OT/PT between those with and without brain surgery in the TBI cohort showed no significant difference between the two groups (Table 5). However, TBI patients who received brain surgery had a significantly longer duration and higher intensity (times) of OT/PT within one year of TBI occurrence (Table 6).

Discussion
In this study, the TBI cohort exhibited a higher risk of subsequent migraine than the propensity score-matched non-TBI cohort. The incidence of migraine following major trauma (ISS ≥ 16) was higher than that following minor trauma (ISS < 16) in the TBI cohort. Hospitalized TBI patients exhibited a higher risk of migraine than those who visited the OPD. Furthermore, surgery or OT/PT did not significantly reduce the risk of migraine. These results suggest that, in addition to providing acute surgical intervention and chronic rehabilitation, physicians should counsel TBI patients regarding adjuvant strategies to prevent subsequent migraine development.

Pathophysiological Links between Migraine and TBI
Whether trauma induces migraine or triggers a pre-existing susceptibility to migraine itself remains unclear. Several factors may be involved in the risk of migraine-type headache, including axonal injury, changes in cerebral autoregulation, and genetic stability [17,[34][35][36]. For example, cellular injury following TBI increases the concentration of extracellular potassium, which can trigger neuronal depolarization and the release of neurotransmitters that promote the development of headaches [37]. Neuroinflammation may also play a role in brain injury [38,39], which is associated with repeated sports-associated TBI events [40][41][42], and headache is a part of its symptom spectrum [40]. Moreover, inflammation and other responses to injury can enhance neuronal excitability [43]. Hyperexcitability of trigeminal nerve branches mediates throbbing head pain in patients with migraine [10].

Effects of the Severity of TBI on the Risk of Migraine
In this population-based study of Taiwanese adults, the TBI cohort exhibited a 1.484-fold increased risk of migraine, which is in accordance with previous findings, suggesting TBI to be a risk factor for migraine [15][16][17]. Compared with TBI patients diagnosed in the OPD or emergency department, hospitalized TBI patients exhibited an increased risk of subsequent migraine. Similarly, compared with TBI patients with ISS < 16, those with ISS ≥ 16 exhibited an increased risk of subsequent migraine. These results suggest that patients with a higher severity of TBI exhibit a higher risk of migraine. However, these results contradict previous findings that mild TBI is associated with a higher risk of migraine [10,15,16,19,29,30]. These discrepant findings may be attributed to several factors. First, various criteria have been used to define the severity of TBI. These include the duration of loss of conscious [44], Glasgow Coma Scale score [5,36,45], and duration of post-traumatic amnesia (PTA). A recent study even identified more than 50 definitions for mild TBI [46]. These varying definitions may lead to differing results. Second, the inclusion criteria and sample selection processes were different in the studies. As the TBI group mainly includes patients with mild TBI, the literature largely includes samples with mild TBI and associated postconcussive disorder. Third, according to Do et al., sociodemographic differences, such as the absence of a third-party insurance program, are responsible for the discrepancies [47]. However, previous studies have not explained why migraine develops more frequently after mild TBI [15,16].
Some studies have assessed the occurrence, longitudinal course, associated factors, and characteristics of headache in more severe TBI patients. For example, one study revealed that patients who continued to experience headaches three months after TBI were more likely to exhibit slow continued recovery, particularly after a year of persistent headaches and particularly if their TBI was moderate or severe [17]. Another study revealed that patients with a history of moderate TBI had higher odds of reporting severe headaches (adjusted odds ratio: 3.89) and migraine-like features (adjusted odds ratio: 15.34) than those with subconcussive exposure, which was limited to mild TBI [44]. Furthermore, a study revealed that moderate and severe TBI can disrupt the blood-brain barrier and thus allow the migration of neutrophils from leaky blood vessels, resulting in neuroinflammation, which plays a key role in the pathophysiology of post-traumatic headache [39]. Thus, moderate or severe TBI may result in more injury and an increased risk of migraine.
We propose some possible explanations for these results. First, the follow-up times and methods for measuring tracking progress after TBI differed in the studies [48]. A recent study revealed that most patients improve within a few days to a few weeks; however, many patients continue to report PCS for months or years, even after very minor head injuries [49]. Walker et al. reported another type of headache course after severe TBI, which is known as delayed-onset headache, the symptoms of which do not manifest until after acute rehabilitation. In their study, the occurrence rate of delayed-onset headaches over the one-year period after discharge was 22% [50]. Second, measuring the progress and outcomes following neuropsychological rehabilitation for mild TBI is challenging because of the variability of baseline symptoms, the subjectivity of many common problems, and the lack of a reliable relationship between objective measures (such as neuropsychological tests and neuroimaging) and the subjective sense of progress or success [51]. Thus, studies with shorter follow-up times or difficulty in tracking may have underestimated the number of patients who developed migraine after moderate or severe TBI. Third, studies on the association between the severity of TBI and pain have reported mixed findings. In these studies, information was collected based on patient reports [30,44]. Hence, multiple factors, such as sampling bias [50], assessment methods, study types, and cultural and language backgrounds [52], can explain the discrepancies observed in the prevalence of post-traumatic headache in different studies. Patients with mild TBI have been reported to be more susceptible to perceiving pain and have a lower pain threshold [38]. Moreover, patients with more severe TBI may have difficulty in reporting or processing their symptoms because of memory disturbance, language deficit, and executive dysfunction. Thus, more reports of migraine may be observed after mild TBI than after moderate or severe TBI. A prospective controlled study assessing the risk of migraine in TBI patients is, therefore, warranted to confirm this association.

Effects of Treatment Modalities for TBI on the Risk of Migraine
To the best of our knowledge, this is the first study to examine the association between treatment modalities for TBI and the risk of migraine by using data from a nationwide population-based database. No significant difference was noted in the risk of migraine between patients undergoing brain surgery and those receiving OT/PT. However, evidence of the association between treatment modalities and the risk of migraine is still lacking. Further studies are warranted to assess the association between treatment modalities for TBI and the risk of migraine.
Many factors can affect recovery from TBI; these include injury characteristics, neuropathological findings, premorbid personality traits, and psychological characteristics [53].
Moreover, several studies have revealed that migraine-like headaches are linked to slow recovery [54][55][56]. Rehabilitation after brain injury can promote recovery through three main approaches: spontaneous improvement that can prevent complications in days to months, increase in neuroplasticity that can result in functional restitution, and compensative maximization of independence and quality of life [20].
Most approaches for treating post-traumatic headache with migraine-like features are derived from those effective in treating migraine headaches [49,57]. Nonpharmacological approaches involve lifestyle modifications, such as exercise, good sleep, hydration, and management of stress or events that can trigger migraine attacks. Managing anxiety may reduce ongoing symptoms [58]. Moreover, managing socioeconomic and family-related stressors plays a crucial role in managing the effects of persistent PCS [49,59]. Furthermore, pharmacological treatment [60], such as acute or preventive medications for primary headache disorders, is useful [19,25,61].

Strengths and Limitations of This Study
Our study has several important strengths. First, this longitudinal study involved a large cohort, providing sufficient power to detect associations and to adjust for a wide range of potential confounders. Second, the baseline characteristics, such as comorbidities, did not differ significantly, thereby decreasing the heterogeneity usually noted in a civilian study population. Third, the follow-up period in our study was quite long (>10 years). This may decrease the possibility of the under-identification of patients who developed migraine in a later period after TBI. Fourth, we not only demonstrated the prevalence of migraine among TBI patients, but we also described the relationship of migraine with the severity of brain injury and treatment modalities. Finally, to increase the validity of our findings, we only included patients who received a diagnosis of migraine from an otolaryngologist or a neurologist.
Our study also has several limitations. First, TBI and migraine were diagnosed based on ICD codes instead of using validated structural diagnostic instruments or the International Classification of Headache Disorders, 3rd edition codes. Moreover, detailed medical records, including OT/PT's treatment intensity, were unavailable in the deidentified claims data. However, to improve the accuracy of our definition of migraine, we only used diagnoses made by otolaryngologists and neurologists. Additionally, we could not identify the severity of TBI based on ICD-9-CM codes. Hence, we used data on ISSs and management levels (e.g., treatment on OPD visits, emergent department visits, or hospitalization) to distinguish the severity of TBI. However, this may not accurately reflect the severity of TBI. Second, data on residual confounders, including genetic, physical, psychological, behavioral, and other socioenvironmental parameters related to different types of migraine, were not available in the NHIRD. However, adjusting for age and sex in the analysis may partially control for this factor. Furthermore, the baseline characteristics did not differ significantly in our study, which may reduce the heterogeneity. Third, despite being derived from a population-based study, our results may not be generalizable to other countries with populations with different ethnicities and backgrounds. Fourth, several studies have revealed that patients with a family history of headache are more likely to exhibit a migraine phenotype than those without this family history [51]. However, we could not assess the effect of family history in the claims database. Finally, because of the retrospective study design, we could not determine the causal relationship between TBI and migraine. Additional prospective trials are warranted to clarify the causal relationship between TBI and migraine and to determine the effects of treatment on the risk of migraine in TBI patients.

Conclusions
This study demonstrated that TBI was associated with a 1.484-fold increased risk of migraine. Moreover, among TBI patients, hospitalization and major trauma (ISS ≥ 16) were associated with 1.557-fold and 1.670-fold increased risks of migraine, respectively. No significant differences were noted between the treatment modalities after TBI. These findings highlight the importance of long-term follow-up after TBI and the need to further assess the underlying pathophysiological link between TBI and subsequent migraine. Table A1. Diagnostic codes (ICD-9-CM and ICD-10-CM codes) for the inclusion and exclusion variables and NHI and ATC codes for medications.